Injectable steroid compositions containing at least 75% benzyl benzoate



a 164 520 INJECTABLE srnnoni coMrosmoNs CONTAIN- ING AT LEAST 75% smart.BENZOATE Raymond Charles Huber, Martinsville, N.J., assignor to Ser. No.233,931 4 Claims.

This invention relates to compositions of matter and more particularlyto new parenterally administrable pharmaceutical compositions comprisingone or more active medicaments and a physiologically acceptablenon-toxic pharmaceutical vehicle, comprised essentially of benzylbenzoate.

The active medicament which may be incorporat d in the novelcompositions of this invention may be any one which is administered foruse in comparatively large unit dosages, for example, rug/ml. to 500mg./ml. and which is soluble in benz yl benzoate. Examples of themedicaments which may be employed in this invention include inter alia,steroid hormones, especially those steroid hormones which exhibitanabolic, estrogenic, androgenic and progestational activity, forexample, l7-hydroxyprogesterone and the esters thereof, testosterone,estradiol and the acid esters thereof, progesterone and its derivativesand A testololactone and its derivatives. In the most preferableembodiment of this invention the active medicament is a steroid hormonealthough other pharmaceutically active compounds may also be employed,with satisfactory results.

Heretofore it has been well recognized in the preparation of.parenterally administrable pharmaceutical compositions that a suitablesolvent must be employed to render the composition injectable. However,as the science of medicine has progressed it has been found thatincreasingly higher dosages of certain medicaments must be employed inthe treatment of certain ailments in order to achieve severaladvantages. Among these advantages can be numbered the prolongation ofactivity of the medicaments involved and the lessening of the totalnumber of individual injections which are needed to obtain the sameresults.

Additionally, it has been found that new chemical modifications ofmedicaments are continually being discovered and the solubility of thesemodified medicaments in the solvents commonly employed, appears to bemore and more limited and it has therefore become increasingly difficultto dissolve these new modified medicaments in parenterally acceptablevehicles. It is well-known that certain pharmamutical vehicles'yieldsatisfactory results at low level medicament concentrations whenemployed in compositions for parenteral administration. Such vehiclesare the vegetable oils such as cotton seed oil, peanut oil, sesame oil,or corn oil, in combination with small amounts of benzyl benzoate.However, when an increased dosage level of the medicaments is employed,along with a correspondingly necessary increased amount ofpharmaceutical vehicle it has been found that certain undesirabledisadvantages exist. j

The undesirable disadvantages which are present when the prior artvehicles are employed with a high dosage level of medicaments, are many.In addition to the prior art vehicles being incapable of solubilizingany great quantities of the medicaments, it has been found that thecompositions heretofore employed produce an undue amount of irritationat the site of injection, when parenterally administered into the animalbeing treated.

It has now been found that the disadvantages encountered in theparenteral administration of high dosage levels of the medicaments ofthis invention can be avoided by employing the novel pharmaceuticalcompositions of United States Patent 0 Fr ice this invention. It hasbeen found that these disadvantages can be overcome by employing benzylbenzoate as the essential component of the pharmaceutical vehicle ofparenterally administrable compositions. The benzyl benzoate has beenfound to be capable of dissolving great quantities of the medicaments ofthis invention and the resulting parenterally administrable compositionemploying this vehicle does not produce undue irritation when injectedinto the animals being treated.

The amount of benzyl benzoate which may be employed in thecompositionsof this invention while still yielding satisfactory results has beenfound to range from about to by volume of the pharmaceutical vehicleemployed. Thus the ratio of benzyl benzoate present in thepharmaceutical vehicle as compared to any other ingredients therein mustbe at least 3 to 1. In the most preferable embodiment of this inventionit has been found that a pharmaceutical vehicle consisting essentiallyof pure benzyl benzoate yields the best results although at lower'levelssatisfactory results are also obtained.

As is common in the art of preparing parenterally administrablepharmaceutical compositions other additives such as preservatives,antioxidants or anesthetics, such as benzyl alcohol and the other likewell known additives may also be included in the pharmaceuticalcompositions of this invention. However, their use herein is permissiveand not mandatory as their incorporation or omission in the finalproduct of this invention does not substantially affect the resultsherein obtained.

The compositions of this invention are easily prepared by merely takingthe desired amount of medicament and dissolving it in the pharmaceuticalvehicle of this invention by any means known in the art, for example, bymere stirring.

The final compositions of this invention are parenterally administrableto the animal being treated. The administration of the composition maybe accomplished intramuscularly, subcutaneously or in any other mannerknown to the art as may be determined in the individual cases whereinthis invention is employed. It has been generally found that the mostpreferable results are obtained when an intramuscular route ofadministration is employed, although other methods of administrationwill also give satisfactory results.

The invention is more particularly illustrated by the followingexamples:

Example 1 Two g. of the acetophenone derivative of16,17-dihydroxyprogesterone are dissolved in 10 ml. of benzyl benzoatewith stirring and warming. The resultant solution is then filled invials of 5 ml. each and sterilized by autoclaving at 121 C. for twohours.

0.25 ml. of the resulting solution is then injected into the vastuslateralis muscle of a rabbit producing a lesion at the'site of theinjection having the size of about 640 cubic millimeters after two days.

\Vhen 2 g. of the acetophenone derivative of 16,17-dihydroxyprogesteroneare dissolved in 4.5 ml. of benzyl benzoate and 5.5 ml. of castor oil inaccordance with the procedure of Example 1 and 0.25 ml. of the resultantsolution is injected intramuscularly into the rabbit a lesion at thesite of injection having a size of 967 cubic millimeters after two days.

Example 2 The procedure of Example 1 is followed except that 2 g. oftestosterone palmitate are substituted for the acetophenone derivativeof l6,l7-dihydroxyprogesterone of Example 1.

0.25 ml. of the resultant solution is injected intramusproduct.

aroma-o cularly into a rabbit producing a lesion at the site ofinjection having the size of about 420 cubic millimeters after two days.When 2 g. of testosterone palmitate are dissolved in a vehicleconsisting of 40% castor oil and 60% benzyl benzoate and the resultantsolution is injected intramuscularly into the rabbit, a lesion at thesite of injection having a size of 610 cubic millimeters is producedafter two days.

Example 3 A 25% solution of progesterone is prepared by dissolving 2.5g. of progesterone in benzyl benzoate to make 10 ml. Sterilization isobtained by autoclaving the solution at 121 C. for 2 hours. When 0.25mg. of this solution is injected into the vastus lateralis muscle of therabbit, a lesion is produced which, after 2 days, measures 672 cubicmillimeters.

When 2.5 g. of progesterone are dissolved to make 10 ml. in a mixture of50% benzyl benzoate and 50% castor oil as the vehicle, and 0.25 ml. ofthis solution is injected into the rabbit muscle, a lesion size of 898cubic millimeters is produced after two days.

Example 4 A 50% solution of hormones is'prepared by dissolving 2.5 g. ofprogesterone and 2.5 g. of l7-hydroxyprogesterone caproate in benzylbenzoate to make 10 ml. of final After autoclaving at 121 C. for 2 hoursto sterilize, 0.25 ml. of the solution is injected into a rabbit muscleand the lesion size is measured after 2 days. A lesion consisting of 572cubic millimeters was produced. When this same hormone combination inthe same proportions Was dissolved in a vehicle consisting of 46% benzylbenzoate and 54% castor oil, a rabbit muscle lesion size of 1047 cubicmillimeters is produced 2 days after injection of 0.25 ml. of testmaterial.

Example A 40% solution of testosterone enanthate is prepared :bydissolving 4.0 g. in benzyl benzoate to make ml. of final volume. Afterautoclaving at 121 C. for 2 hours to sterilize, 0.25 ml. of the solutionis injected into the vastus lateralis muscle of the rabbit and thelesion size is measured after 2 days. A lesion consisting of 847 cubicmillimeters is produced. I

When this same quantity of hormone is dissolved in a vehicle consistingof benzyl benzoate and 80% sesame oil and 0.25 ml. is injected a lesionsize of 1441 cubic millimeters is produced.

Example 6 A 5% solution ofA btestololaetone is prepared by dissolving 50mg/ml. in benzyl benzoate and after autoclaving to sterilize, 0.25 ml.of the solution is injected I Example 7 15 mg. of A -testo-lolactone isdissolved in a solution comprised of 7.5 ml. of benzyl benzoate and 2.5ml. of castor oil. The resultant solution is sterilized, then filled invials of 5 ml. each and sterilized by autoclaving at 121 C. for 2 hours.The injectable solution may then be administered to the patient beingtreated.

This invention may be variously otherwise embodied Within the scope ofthe appended claims.

What is claimed is:

1. A parenterally administrable pharmaceutical composition compris-ingthe acetophenonide of 16,17-dihydroxyprogesterone and a physiologicallyacceptable nontoxic pharmaceutical vehicle wherein at least by volume ofsaid vehicle is benzyl benzoate.

2. A parenterally administrable pharmaceutical composition comprisingtestosterone palmitate and a physiologically acceptable non-toxispharmaceutical vehicle wherein at least 75% by volume of said vehicle isbenzyl benzoate.

3. A parenterally administrable pharmaceutical composition co-mprisingtestosterone enanthate and a physiologically acceptable non-toxicpharmaceutical vehicle wherein at least 75 by volume of said vehicle isbenzyl benzoate.

4. A method of administering a large single dosage of a steroid whichcomprises parenterally administering to the patient being treated acomposition comprising a steroid selected from the group consisting of17-hydroxyprogesterone, the caproate ester of 17-hydroxyprogesterone,testosterone, the enanthate ester of testosterone, the palmitate esterof testosterone, estradiol, progesterone, and A -testololactone, and apharmaceutical carrier, said carrier being at least 75% by volume ofbenzyl benzoate.

References Cited in the file of this patent Chemical Abstracts, vol. 52,p. 7620b, 1958 (abstr. of Gerosa et al., Ann. Chim., Rome, 47, pp.1388-1393 (1957)).

Chemical Abstracts, vol. 42, p. 9084g, 1948.

Chemical Abstracts, vol. 47, p. 6611d, 1953.

Merck Index, 7th ed., 1960, p. 137.

U.S. Dispensatory, 25th ed., 1955, p. 160.

Sax: Handbook of Dangerous Materials, p. 45, Reinhold, New York, 1951. j

4. A METHOD OF ADMINISTERING A LARGE SINGLE DOSAGE OF A STEROID WHICHCOMPRISES PARENTERALLY ADMINISTERING TO THE PATIENT BEING TRETED ACOMPOSITION COMPRISING A STEROID SELECTED FROM THE GROUP CONSISTING OF17-HYDROXYPROGESTERONE, THE CAPROATE ESTER OF 17-HYDROXYPROGESTERONE,TESTOSTERONE, THE ENAANTHATE ESTER OF TESTOSTERONE, THE PLAMITATE ESTEROF TESTOSTERONE, ESTRADIOL, PROGESTERONE, AND $1-TESTOLALACTONE, AND APHARMACEUTICAL CARRIER, SAID CARRIER BEING AT LEAST 75% BY VOLUME OFBENZYL BENZOATE.